Postgrad Med J 1999;75:579–584 © The Fellowship of Postgraduate Medicine, 1999

Classic diseases revisited Postgrad Med J: first published as 10.1136/pgmj.75.888.579 on 1 October 1999. Downloaded from

Progressive supranuclear palsy (Steele-Richardson-Olszewski disease)

Huw R Morris, Nicholas W Wood, Andrew J Lees

Summary Progressive supranuclear palsy (PSP) is an important but probably under- Progressive supranuclear palsy is diagnosed neurodegenerative syndrome. The anatomy of PSP overlaps with that a neurodegenerative disease of Parkinson’s disease (PD) and its microscopic pathology is similar to that of which aVects the brainstem and Alzheimer’s disease. The distinctive clinical features of PSP, in large part due to basal ganglia. Patients present brainstem involvement, make the diagnosis reasonably straightforward once it with disturbance of balance, a dis- has been considered by the examining physician. order of downward gaze and L-DOPA-unresponsive - Historical aspects sonism and usually develop pro- gressive dysphagia and dysarthria PSP was first described as a distinct syndrome by John Steele, J CliVord Rich- leading to death from the compli- ardson and Jerzy Olszewski in 1963 following Richardson’s clinical observations cations of immobility and aspira- on several patients with a unique syndrome in Toronto in the late 1950s.12 tion. Treatment remains largely Although experienced neurologists at that time were unable to categorize the supportive but, potentially, treat- syndrome, a number of reports from the early 20th century indicate that it is not ments based on cholinergic a new disorder.34An early photograph showing the typical posture of PSP has may be useful. As in been identified,5 and review of the film archives of Denny-Brown have shown a Alzheimer’s disease, the neuronal number of cases which can be identified to have been early cases of PSP.6 It is degeneration is associated with also likely that one of MacDonald Critchley’s cases of ‘arteriosclerotic pseudo- the deposition of hyperphosphor- ’, described in the 1920s, also had PSP.7 The clinical skill of Steele ylated as neurofibril- and Richardson together with the expertise of Olszewski in delineating lary tangles but there are brainstem anatomy allowed this ‘new’ clinicopathological entity to be described important distinctions between and their seminal report was followed by many case reports and case series from the two diseases. Evidence from around the world.8 The documentation of these individual cases and case series familial fronto-temporal demen- through the 1960s, 1970s and 1980s have been followed by more recently by tia with parkinsonism linked to epidemiological studies.910 chromosome 17 suggests that deposition is a primary Clinical diagnosis pathogenic event in some neuro- http://pmj.bmj.com/ degenerative diseases. The under- PSP is frequently misdiagnosed, most commonly as PD, but when PSP is con- standing of the mechanism of tau sidered, its distinctive features usually make it possible to make a confident deposition in progressive supra- diagnosis (box 1). Most patients present with gait disturbance and unsteadiness nuclear palsy is likely to be of with a tendency to fall backwards. The gait has a characteristic reeling or stag- importance in unravelling its aeti- gering quality, due to the stiV posture of the trunk and neck with irregular large ology. steps forwards, which allow a distinction to be made from the veering broad based gait of . Keywords: progressive supranuclear palsy; Some patients present with early complaints of visual disturbance which are on October 1, 2021 by guest. Protected copyright. Steele-Richardson-Olszewski disease; tau protein related to fixation instability and disruption of the control of saccadic eye move- ments. Unfortunately, as visual acuity itself is not aVected by PSP, these symp- toms may be initially thought to be psychogenic in origin until the typical distur- bance of downward gaze emerges. The neuro-ophthalmological features of patients with established PSP are usually clear cut.11 Frontalis overactivity and a diminution of the blink rate to less than 4/minute lead to a ‘surprised’ facial appearance. Eye opening may be impaired either by active involuntary contrac- tion of orbicularis oculi () or by inability to voluntarily open the eyes (‘ of eyelid opening’) (figure 1).12 Fixation on a stationary object may be interrupted by visible constant velocity saccadic intrusions in which the gaze is diverted briefly away and then back to the target, described as square wave jerks.13 In the earliest stages of the disease there may be slowness of vertical sac- cadic eye movements which progress to limitation of downwards vertical National Hospital for and 11 , Queen Square, London saccadic eye movements and then to a complete vertical gaze palsy. The doll’s WC1N 3BG, UK head manoeuvre may be used to generate a normal vertical vestibular-ocular H R Morris response demonstrating the integrity of the third nuclei and confirming NWWood that the eye is supranuclear. Some limitation of upgaze is a A J Lees frequent accompaniment of normal and may be seen in PD; limitation of downgaze is a much more specific finding suggestive of PSP. In the late stages of Correspondence to Dr AJ Lees the disease, involvement of the horizontal eye movement system may lead to a Accepted 14 May 1999 complete supranuclear gaze palsy.11 580 Morris, Wood,Lees

Ta bl e Clinical features diVerentiating Parkinson’s disease (PD) and progressive Postgrad Med J: first published as 10.1136/pgmj.75.888.579 on 1 October 1999. Downloaded from Diagnostic criteria for PSP18 supranuclear palsy (PSP)

Mandatory inclusion criteria PSP PD x postural instability with falls in the Balance Early postural instability Initially well preserved gait and balance first year of symptoms Speech Growling dysarthria Hypophonic dysarthria x slowing of vertical saccadic eye Facial appearance Taut Loose movements (clinically possible); Extrapyramidal Axial rigidity; relatively well Distal rigidity and bradykinesia; decrement vertical supranuclear gaze palsy features preserved fine finger movements; in amplitude and speed of fine finger (clinically probable) in <10% movements; tremor in 95% through disease course Supportive criteria Symmetry Symmetry of symptoms and signs Asymmetry of onset and persistent asymmetrical signs x frontal/sub-cortical cognitive L-DOPA Little response to L-DOPA Excellent response to L-DOPA dysfunction x axial rigidity x pseudobulbar dysphagia and dysarthria x blepharospasm/apraxia of eyelid The extrapyramidal features of PSP are distinctive and should be separable opening from PD (table). Lack of spontaneous and associative movements, dysarthria and facial immobility may suggest the diagnosis of PD during conversation and Box 1 history taking. However, careful observation and examination often reveals a taut spastic face, a growling dysarthria, neck held in extension with axial rigidity, and a symmetrical relatively mild distal bradykinesia, often in the presence of normal muscle tone and in the absence of rest tremor. PSP rarely responds to L-DOPA therapy and it should be considered in the diVerential diagnosis of L-DOPA unresponsive Parkinson’s syndrome along with vascular pseudo-parkinsonism, corticobasal degeneration, and multiple system . While amnesia resulting from mesial temporal damage is not a feature of PSP, history from relatives and carers and specific bedside tests may reveal more sub- tle cognitive impairment. Functional imaging and clinical psychological studies show frontal hypometabolism and a deficit in frontal psychological tasks, respectively.14 There may be a prodromal history of personality change or diY- culty in carrying out day-to-day tasks which reflect frontal/subcortical disinhibi- tion, apathy or diYculties in or judgement. Emotional lability and aggressive outbursts are common. Bedside testing may reveal diYculty in performing a three-stage command and markedly impaired verbal fluency in ini- tial or category naming tests. Neuropsychological testing is often characterised by profound slowing of responses, with correct replies eventually being produced when suYcient time is allowed.15 The final stages of PSP are usually dominated by an increasingly severe dys- arthria and dysphagia. These features are usually described as being part of a pseudo-bulbar palsy, as brisk jaw and facial jerks may be present. However,

the aetiology of these bulbar features is probably multifactorial with a http://pmj.bmj.com/ contribution from damage to extrapyramidal, pyramidal and brainstem reticu- lar structures.

DiVerential diagnosis

In addition to PD, a number of other conditions may be misdiagnosed as PSP, usually on the basis of a parkinsonian syndrome with gaze abnormalities (box 2). These conditions include corticobasal degeneration, multiple system on October 1, 2021 by guest. Protected copyright. atrophy, progressive subcortical due to disease, some forms of autosomal dominant cerebellar ataxia (particularly SCA-7 and SCA-2), and vascular pseudo-parkinsonism. Whipple’s disease is also important to consider since, although rare, it is a treatable cause of progressive neurological disease with a gaze palsy and may be diagnosed by small bowel biopsy or cerebrospinal fluid polymerase chain reaction for Tropheryma whippeli. In younger patients, Niemann-Pick disease type C and occasionally other storage disorders may present in a similar way to PSP. In the elderly population, vascular pseudo-parkinsonism is common and worth considering, particularly in view of the potential to identify modifiable risk factors. Vascular pseudo-parkinsonism may be identified by a shuZing small-stepped gait with a good arm swing (‘lower body parkinsonism’; ‘marche à petit pas’),16 and relative sparing of axial and upper limb function. Rarely, neurosyphilis and compressive mid- lesions may produce a neuro-ophthalmologic disorder and these conditions should be excluded with syphilis serology and neuro- imaging.17 Operational criteria for the research diagnosis of PSP have recently been for- Figure 1 Facies of a patient with PSP mulated (box 1).1 These criteria focus on postural instability and evidence of showing asymmetric blepharospasm, damage to the vertical gaze system as the two core features of the disease frontalis overactivity and taut dystonic facial expression (reproduced with the patient’s together with the absence of clinical or investigative features suggesting an alter- permission) native diagnosis. These criteria have been reported to have an 80% sensitivity Progressive supranuclear palsy 581

and specificity but potentially may exclude patients with PSP who develop Postgrad Med J: first published as 10.1136/pgmj.75.888.579 on 1 October 1999. Downloaded from Causes of a vertical behavioural or personality change significantly before the occurrence of a gait supranuclear gaze palsy disorder and those who have atypical disease without a supranuclear gaze palsy.19 20 x progressive supranuclear palsy x corticobasal degeneration x fronto-temporal with Epidemiology parkinsonism linked to chromosome 17 x prion diseases (Creutzfeld-Jakob A prevalence of 1.4/100 000 has been reported from New Jersey, but this is likely disease, progressive subcortical gliosis) to be an underestimate because of the exclusion of ‘atypical parkinsonism’, mis- x autosomal dominant cerebellar ataxias diagnosed as PD.921The median life expectancy from symptom onset to death (particularly SCA-2 and SCA-7) is 9 years.9 The 1991 UK Parkinson’s Disease Society brain bank study showed x Whipple’s disease that 25% of clinically diagnosed PD cases, had alternative pathological x Niemann-Pick disease type C x vascular pseudo-parkinsonism diagnoses; atypical PSP was the commonest misdiagnosis accounting for around 21 x compressive midbrain syndromes 6% of the cases in this series. Studies of this type suggest that PSP may be sub- (Parinaud syndrome), eg, pinealoma, stantially under-diagnosed and that the true population prevalence of PSP may glioma be much greater than has been reported. Case-control studies have not demon- x neurosyphilis strated any definite risk factors for the disease,22 23 but there is increasing interest in the role of genetic susceptibility. Box 2

Pathology

PSP has a distinctive topographical and molecular pathology. The cellular hall- mark of the disease is neurofibrillary degeneration; and the distribution and intensity of damage to the brainstem and basal ganglia is used to pathologically define the syndrome.24 The main lesions are in the pars compacta and reticulata, the , the , and the midbrain and pontine reticular formation. This destruction of midbrain and pontine structures leads to identifiable changes of brainstem atrophy on with dilatation of the cerebral aqueduct, thinning of the midbrain tegmentum and dilatation of the fourth ventricle (figure 2).25 A recent blinded study indicates that dilatation of the and a midbrain diameter of less than 17 mm are useful in distinguishing PSP from other atypical parkinso- Figure 2 Glial stained section through the midbrain of a patient with PSP showing nian syndromes (A Schrag, personal communication). midbrain atrophy with dilation of the The renaissance of neurosurgical approaches to PD and the study of primate cerebral aqueduct and gliosis of the models of extrapyramidal dysfunction have led to reconsideration of the substantia nigra and peri-aqueductal region. Courtesy of Dr T Revesz, Institute of functional pathology of the basal ganglia. Current models are inconsistent in their Neurology, London explanation of the symptomatology of potentially the simplest disease, PD,26 and the functional anatomy of PSP is even more complex and poorly understood. PSP involves damage to both the putaminal and caudate striatal projections of the http://pmj.bmj.com/ substantia nigra pars compacta (SNpc), the ventrolateral and dorsomedial areas, respectively.27 This homogenous depletion of the SNpc is in contrast to the vent- rolateral nigral selectivity of PD, which preferentially damages the putaminal nigrostriatal projection. This anatomical diVerence can be visualised in vivo with PET imaging of loss of 18F-DOPA uptake by both caudate and putaminal nigros- triatal nerve terminals in PSP as opposed to preferential loss of putaminal uptake 28

in PD, (figure 3). The treatment of PD with L-DOPA is thought to lead to a on October 1, 2021 by guest. Protected copyright. restoration of normal output from the basal ganglia with attenuation of pallidothalamic GABAergic inhibition, but in PSP the major output centres of the basal ganglia, the substantia nigra pars reticulata and the globus pallidus internus, are already severely damaged by the underlying disease process.29 The subthalamic nucleus has been shown to be overactive in PD and lesioning or high frequency stimulation (producing suppression) of the subthalamic nucleus is proving to be a highly successful manoeuvre in ameliorating the tremor, bradyki- nesia and rigidity of PD.30 The subthalamic nucleus is also damaged in patients with PSP.31 This destruction of the major basal ganglia output areas and the sub- thalamic nucleus, which are intact and overactive in PD, presumably partly con- tributes to the clinical diVerences between PSP and PD (figure 4). The brainstem reticular pathology in PSP includes the midbrain and pontine nuclei involved in the supranuclear control of gaze: the rostral interstitial nucleus of the medial longitudinal fasciculus, the interstitial nucleus of Cajal, the nucleus of Darkschewitsch, and the raphé nucleus interpositus.32 33 Additionally, the cholinergic pedunculopontine nucleus is damaged, which is thought to have a role in the control of and balance.34 Contrary to the earliest reports, corti- cal pathology does occur in PSP and is most marked in the deepest cortical lay- ers of the precentral gyrus, occurring to a lesser extent in pre-frontal areas.35 However, clinical and functional imaging data suggest that the major cognitive deficit in PSP is in frontal function and given the distribution of cortical 582 Morris, Wood,Lees

Figure 3 18-FDOPA uptake scan showing Postgrad Med J: first published as 10.1136/pgmj.75.888.579 on 1 October 1999. Downloaded from loss of uptake in the putamen in PD and both caudate and putamen in PSP. Courtesy of Dr P Piccini and Prof D Brooks, MRC Cyclotron Unit, Royal Postgraduate Medical School, Hammersmith Hospital, London

neurofibrillary tangle formation, this presumably relates in part to a disturbance of reciprocal thalamocortical connections.14 15

Molecular pathology

PSP is one of a group of neurofibrillary tangle disorders.36 Corticobasal degen- eration, post-encephalitic parkinsonism, post-traumatic parkinsonism, some forms of and the parkinsonism dementia complex of Guam, all involve the deposition of hyperphosphorylated tau protein as neurofi- brillary tangles.36 The discovery of autosomal dominant in the tau causing some forms of frontotemporal dementia has focused interest on the possibility that primary abnormalities in tau protein are responsible for neuronal degeneration in these conditions.37 This suggests that which alter the deposition of tau protein may be the most eVective way to modify the underly- ing disease process. The neurofibrillary tangles deposited in PSP can be distinguished from those seen in Alzheimer’s disease in a number of ways. Tau http://pmj.bmj.com/ neurofibrillary tangles appear most commonly as globose tangles under the light microscope, in contrast to the flame-shaped tangles of Alzheimer’s disease. Under the electron microscope, the tangles in PSP appear as straight filaments with a diameter of 15–18 nm.38 In vitro work suggests that these straight filaments are preferentially formed by isoforms of the alternatively spliced tau gene containing four binding domains,39 and this theory is supported by 40 recent work confirming that tau protein in PSP has four repeat isoforms. In on October 1, 2021 by guest. Protected copyright. Alzheimer’s disease, tau is identified on immunoblotting to have three abnormal major protein bands, at 55, 64 and 68 kDa, whereas the major bands in PSP are at 64 and 68 kDa. This has also been shown to be consistent with the expression of four repeat isoforms of the tau gene in PSP, as opposed to expression of all six isoforms of the tau gene in Alzheimer’s disease.40 The link between a genetic predisposition to PSP and the diVerential isoform expression of the tau gene may be the key to explaining the pathogenesis of PSP.

Genetics Figure 4 Connectivity in the basal ganglia. While in PD the substantia nigra pars 41–46 compacta (SNc) is preferentially aVected, in A number of families have been described with autosomal dominant PSP, PSP the major outputs to the thalamus although to date neither a linked chromosomal locus nor a causative gene muta- (THAL), the substantia nigra pars reticulata tion have been identified. Analysis of sporadic PSP cases have demonstrated that (SNr) and globus pallidus internus (GPi) are also aVected in addition to the one form (the A0 allele) of a variable non-protein coding site (intronic polymor- subthalamic nucleus (STh) which is phism) within the tau gene occurs more frequently in patients with PSP than overactive in PD. Other abbreviations: 47 (CTX), (STR), controls. This may be a predisposing factor to PSP which, similarly to the globus pallidus externus (Gpe). Courtesy of apolipoprotein E å4 allele in Alzheimer’s disease, increases the risk of develop- Dr Andrew Gillies, Institute for Adaptive & ing PSP but is in itself neither necessary nor suYcient to cause the disease. Neural Computation, Division of Informatics, University of Edinburgh, Although this polymorphism lies before an alternatively spliced protein coding Edinburgh exon of the tau gene, it is unknown whether this polymorphism or an adjacent Progressive supranuclear palsy 583

linked area has an eVect on the alternative splicing of tau and whether this is Postgrad Med J: first published as 10.1136/pgmj.75.888.579 on 1 October 1999. Downloaded from important in the pathogenesis of the disease.

Treatment

Supportive treatment is the mainstay of management as the disease is relentlessly progressive. Explanation of the diagnosis and contact with patient support groups may be of benefit, particularly as patients may have been misdiagnosed as having PD or other disorders earlier in their illness. Physiotherapy and occu- pational therapy are of importance in helping with aids for balance and avoidance of falls. The early identification of problems with swallowing is important and this should prompt referral to speech therapy services for swallowing assessment and advice on appropriate measures to avoid the compli- cations of aspiration.48 Some patients and their families benefit from the insertion of a percutaneous gastrostomy tube but decisions on invasive interven- tions of this type should take into account the patient’s and families’ wishes in the context of the overall quality of life. Additional communication aids such as light-writers are usually not of benefit because of the concurrent eye movement disorder. Patients usually do not derive great benefit from medication due to widespread damage to structures in the basal ganglia.49 Early reports sug- gested that amantadine may be of more benefit in improving the motor deficits in PSP, but this has not been subject to a formal randomised trial and the response is at best modest. Most interest in PSP has centred on the use of cholinergic treatments, particularly because of the suggestion that cholinergic nuclei may be responsible for the problems with balance.50 However, although oral physostigmine and cholinergic agonists do not produce a useful symptomatic benefit in PSP,51 52 intravenous physostigime has been shown to improve cerebral metabolism,53 and some measures of neuropsychometric and oculomotor performance.54 These data suggest that, if significant enhancement of central cholinergic transmission can be achieved, some symp- tomatic improvement might be attained. Adrenergic agents have also been used in PSP because of the adrenergic deficit resulting in part from damage to the locus coeruleus.55 Although these agents were initially thought to improve motor performance, this has not been replicated and their use has been limited by the occurrence of cardiovascular side-eVects.55 56

Conclusions

PSP is a distinctive syndrome both clinically and pathologically and should be

relatively easily diagnosed once considered by the clinician. The greater under- http://pmj.bmj.com/ standing of the tau gene and tau protein suggests that in the next few years there will be a much clearer understanding of the pathology and aetiology of this con- dition, which should lead to new potential disease-modifying agents. In the shorter term, cholinergic agents may emerge as useful symptomatic treatments for this disease. Currently, accurate diagnosis and the sympathetic provision of supportive care are the most important issues for the practising physician. on October 1, 2021 by guest. Protected copyright. We are grateful to Dr JC Steele for helpful discussion. HRM is an MRC Clinical Training Fellow and sup- ported by the PSP (Europe) Association. The PSP (Europe) Association provides support and advice for PSP patients and carers, and can be reached at The Old Rectory, Wappenham, Nr Towcester, Northamptonshire NN12 8SQ, UK.

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